{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:18:20Z","timestamp":1778858300470,"version":"3.51.4"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006483","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Navitoclax, an oral small molecule BCL\u2010X\n                    <jats:sub>L<\/jats:sub>\n                    \/BCL\u20102 inhibitor evaluated in myelofibrosis, was assessed through integrated PK\/PD modeling to guide starting dose and dose\u2010reduction decisions when combined with ruxolitinib. An integrated sequential PK\/PD model was developed to describe the relationships between navitoclax and ruxolitinib exposure, platelet count, and spleen volume. Simulations were conducted to assess spleen volume reductions of \u2265\u200935% at week 24 (SVR\n                    <jats:sub>35W24<\/jats:sub>\n                    ) and incidences of \u2265 grade 3 or grade 4 thrombocytopenia. The population PKs were adequately characterized by two\u2010compartment models, and the subsequent integrated PK\/PD model adequately described the platelet and spleen volume data. Model simulations indicated that the incidence of \u2265 grade 3 or grade 4 thrombocytopenia during a weekly ramp\u2010up from navitoclax 100 to 200\u2009mg once daily (QD) was similar to that predicted with a flat 200\u2009mg QD starting dose. Simulations suggested that reducing doses of navitoclax by 25\u2009mg for patients with baseline platelet counts \u2264\u2009150\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    \/L (starting at 100\u2009mg) and by 50\u2009mg, with an additional 25\u2009mg if needed, for those &gt;\u2009150\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    \/L (starting at 200\u2009mg) effectively minimized \u2265 grade 3 thrombocytopenia while maintaining SVR\n                    <jats:sub>35W24<\/jats:sub>\n                    . Integrated PK\/PD model simulations suggested that a flat starting dose of navitoclax 200\u2009mg for baseline platelets &gt;\u2009150\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    \/L, and 100\u2009mg for \u2264\u2009150\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    \/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Dose reductions of 25\u2009mg for the 100\u2009mg start and 50\u2009mg (plus 25\u2009mg if needed) for the 200\u2009mg start optimized the benefit\u2013risk balance.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70260","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T14:48:51Z","timestamp":1778424531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Semi\u2010Mechanistic\n                    <scp>PK<\/scp>\n                    \/\n                    <scp>PD<\/scp>\n                    Modeling of Platelets and Spleen Volume With Navitoclax in Combination With Ruxolitinib in Patients With Myelofibrosis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-6062","authenticated-orcid":false,"given":"Akshanth R.","family":"Polepally","sequence":"first","affiliation":[{"name":"Clinical Pharmacology, AbbVie  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5059-9427","authenticated-orcid":false,"given":"Aline","family":"Goebel","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie Deutschland GmbH Co. KG  Ludwigshafen am Rhein Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maulik","family":"Patel","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6879-6557","authenticated-orcid":false,"given":"Carla","family":"Biesdorf","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jalaja","family":"Potluri","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-0449","authenticated-orcid":false,"given":"Rajeev M.","family":"Menon","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie  North Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9434-647X","authenticated-orcid":false,"given":"Sven","family":"Mensing","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie Deutschland GmbH Co. KG  Ludwigshafen am Rhein Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0884-9976","authenticated-orcid":false,"given":"Benjamin","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, AbbVie Deutschland GmbH Co. KG  Ludwigshafen am Rhein Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201007\u20105836"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042\u20107158.2012.01526.x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2020.100691"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102007\u201004\u2010083501"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017423"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114363"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.10.038"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.02188"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010014\u20102530\u20109"},{"key":"e_1_2_11_11_1","unstructured":"\u201cDrug Approval Package for Jakafi (Ruxolitinib) Tablets \u201dClinical Pharmacology and Biopharmaceutics Review (S); Application Number: 202192Orig1s000."},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110556"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110557"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bneo.2024.100056"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","unstructured":"F.Passamonti J. M.Foran A.Tandra et\u00a0al. \u201cPreliminary Safety and Efficacy of Navitoclax Plus Ruxolitinib in JAK Inhibitor\u2010Na\u00efve Patients With Myelofibrosis From the Multicenter Open\u2010Label Phase 2 Study (REFINE) \u201d(2025) Submitted for publication in Hematological Oncology.","DOI":"10.1002\/hon.70180"},{"key":"e_1_2_11_16_1","unstructured":"\u201cA Phase 2 Open\u2010Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Subjects With Myelofibrosis (REFINE) \u201dNational Library of Medicine (US) https:\/\/clinicaltrials.gov\/study\/NCT03222609."},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.102"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1729-7"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010017\u20103366\u2010x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637\u2010010\u20109437\u2010z"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70260","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70260","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T14:48:54Z","timestamp":1778856534000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/psp4.70260"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70260","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"2026-03-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70260"}}